Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.757893
Title: Molecular regulation of p53-dependent tumour suppressor responses by the p53 binding protein 1
Author: Cuella-Martin, Raquel
ISNI:       0000 0004 7430 7021
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Abstract:
The tumour suppressor p53 binding protein 1 (53BP1), a fundamental node in DNA double strand break (DSB) repair, was identified as a p53-interacting protein over two decades ago. However, its contribution to p53-dependent responses has remained largely enigmatic. Here, using a combination of detailed structure-function approaches and in vivo analyses I aim to unravel this aspect of 53BP1 functionality. I showed 53BP1 to enhance genome-wide p53-dependent transactivation events in response to multiple stress stimuli. Oligomerised 53BP1 relies on the tandem BRCT domain, dispensable for 53BP1-driven DSB repair, to bridge dual interactions with p53 and the ubiquitin specific protease 28 (USP28). These interactions are both essential for 53BP1-dependent modulation of p53 functionality. Indeed, the cooperation between 53BP1 and USP28 is required for proficient p53-dependent G1/S checkpoint and senescence responses. Mechanistically, the action of the USP28-53BP1 complex involves differential ubiquitination events that ultimately stimulate p53's ability to bind the responsive elements (RE) in its target genes. Furthermore, I demonstrated 53BP1-driven p53 modulation to function independently of 53BP1's well-described DSB repair roles, and be separable by specific point mutations within 53BP1 architecture. Translation to in vivo mouse models revealed 53BP1-driven DSB repair to be responsible for 53BP1's role in the physiology of the immune system, while functional 53BP1-p53 connections result in effective quality control of chromosomal dosage upon defective mitotic division. Collectively, my findings define 53BP1 as an integral node in genome stability control, driving efficient DSB repair and mitotic surveillance mechanisms.
Supervisor: Chapman, J. Ross Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.757893  DOI: Not available
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